Clefts of the lip and palate (CLP) are one of the most common craniofacial anomalies, with a rate of 1:650 in the United States population. Over 250 genetically based syndromes exist which include cleft lip or palate as a feature of their clinical presentation. Since the fall of 1993, we have been collaborating with the Lancaster Cleft Palate Clinic in Lancaster, PA. This project is a large scale molecular epidemiological study, involving the comprehensive mapping of highly informative DNA markers, utilizing the clinical population from the Lancaster Cleft Palate Clinic and affiliated clinics. In the past year we initiated recruiting efforts at Washington University, St. Louis and at the University of North Carolina, Chapel Hill. Semiautomatic gene mapping technologies developed by MGES in ongoing CLP studies are being applied to map gene/genes responsible for clefting. We completed molecular marker typing for several candidate regions based on previous reports in the literature and are initiating statistical analyses on these regions. Preliminary results indicate support for a region of chromosome 2 in the vicinity of the transforming growth factor alpha gene. We have also nearly completed the laboratory phase of a scan of the entire human genome using a sample based on Lancaster families collected by the end of 1996, and are beginning the computerized scoring component of these gel analyses, with statistical analyses pending early in the following year. We also completed a small statistical analysis project aimed at evaluating the bias and degree of reproducibility of five raters making 12 craniofacial measurements as part of our routine clinical evaluation of cleft-affected subjects and their families.